Paul Richardson, MD
Dana Farber Cancer Institute
Interview Date: July 18, 2022

The field of multiple myeloma is moving quickly. In this show, Dr. Paul Richardson shares many updates in the field of myeloma research. He reviewed the results of the DETERMINATION trial which sought to answer the long-term question - is early transplant better than later or no transplant? The study omparied RVD plus or minus early stem cell transplant, finding that there was a signficant difference in progression free survial, but not in overall survival. He shared interesting findings that may bring us to more personalized use of transplant - that obese patients do worse with transplant vs. normal BMI patients, that 4;14 patients may benefit from transplant but del17p patients not as much, and that patients who achieve MRD negativity with or without transplant do better overall. Clearly, the message is that we can personalize therapy including the use of transplant in better ways. He reviewed other key drugs making progress including melfufen, BLENREP, ibderdomide, other celMODs, and CAR T and bispecific therapies. Staying up-to-date on myeloma therapies is essential as the field continues to move quickly as was readily apparent in this show.

Thanks to our episode sponsor

Jenny: Welcome to today's episode of the HealthTree Podcast for Multiple Myeloma, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom. We'd like to thank our episode sponsor, GSK, for their support of this program.

Now, you may have noticed last week, we made a major announcement with a formal name change from Myeloma Crowd to HealthTree for Multiple Myeloma. We did this to converge our foundation name with the name of many of our tools, including HealthTree Cure Hub and HealthTree University, to reduce confusion.

 

One of the programs I'd like to share today before we get started on our show, is our HealthTree Myeloma Coach Program. If you are in need of one-on-one support, whether you're newly diagnosed or you're relapsed, we have over 190 HealthTree Myeloma Coaches who can help you either short term or long term. You can pick your own coach and use them for as long as you need. It's a wonderful program if you need specific support like for stem cell transplant, or if you need help on a particular type of therapy, or financial support, or that type of thing.

 

The coach program is just fantastic. We have an annual coach summit every year with our coaches. It's coming up next week in Park City in Utah for us. We are excited to be meeting with the coaches. We provide them with additional education and share experiences to better help you.

Now, on to our show.

Now in myeloma, we know that things are moving very quickly. We have with us today Dr. Paul Richardson who was a key myeloma speaker at the recent ASCO conference. ASCO is the conference that covers all cancers. It's the largest oncology conference in the world. He'll be providing us with a mid-year review of many of the key happenings in myeloma. We have a lot to cover in today's show. Welcome, Dr. Richardson.

Dr. Richardson: Jenny, it's my pleasure. Thank you very much for inviting me to join today. Please, Jenny, we've known each other for a very nice long time. Please call me Paul. It's lovely to be on your show. As always, a privilege to join you.

Jenny: Thank you so much for joining. I'm going to give a little brief introduction for you before we get started. Dr. Paul Richardson is the R.J. Corman Professor of Medicine at Harvard Medical School, and the attending physician in the Division of Hematologic Oncology and the multiple myeloma and bone marrow transplant service at the Dana-Farber Cancer Institute. Dr. Richardson is the Clinical Program Leader and Director of Clinical Research for Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute.

He's also Chairman of the Multiple Myeloma Committee for the Alliance and Alliance and Alliance Foundation for Clinical Trials, and a Myeloma Steering Committee Member of the National Cancer Institute. He's an Editorial Board Member for Publications such as Clinical Cancer Research, Journal of Clinical Oncology, American Journal of Hematology Oncology, Journal of Oncology and many, many others.

Dr. Richardson is a very distinguished myeloma specialist. He’s a very influential figure in the new drug development approval process, having led many large Phase III clinical trials to get drug approval for many of the therapies like bortezomib, panobinostat, daratumumab, carfilzomib, selinexor, and others.

Dr. Richardson received the Earnest Beutler Lecture and Prize from the American Society of Hematology or ASH for his translational advancements and achievements and enabling clinical science in multiple myeloma. He's also recognized and appreciated by the Patient Advocacy Committee as a recipient of the Robert A. Kyle Lifetime Achievement Award by the International Myeloma Foundation for his work that's resulted in significant advances and research treatment and care of myeloma patients around the world.

Dr. Richardson, we're so happy to have you back on the program. We've done this before with you, this mid-year review. There's so much going on.

Why don't we get started with what you led with at the ASCO conference which was this DETERMINATION trial?

Dr. Richardson: It's my pleasure, Jenny. Thank you for that very kind introduction. I think the bottom line is I'm blessed to work with a fabulous team at Dana-Farber. We have a uniquely strong translational program, which is led by ideas from the laboratory, and brings them to the bedside for our patients. That's been an amazing journey over the last 20 plus years.

The momentum, and in fact, I would argue, has increased by recognizing that we still face enormous challenges with myeloma. Whilst there's great hope, I think it's very fair to listeners, in particular to patients and caregivers, to appreciate that.

As you know, Jenny, we've come a long way, but we've got a long way still to go. Particularly, for high-risk myeloma, the challenges are very real. We've seen amazing progress with standard-risk disease, but high-risk disease remains an area that I think is arguably, an unmet medical need still.

Having said that, progress in high-risk diseases has been made. I think one of the most interesting things about the therapeutic landscape is how can we adapt treatments to best meet the challenge of high-risk disease at the same time adapt the treatment to best suit standard-risk patients or patients with lower risk issues, recognizing that because myeloma remains unfortunately, at the moment at least, an incurable disease.

Obviously, calling something low-risk and high-risk to my mind is a little bit of an oxymoron. But nonetheless, I think it is fair to say high-risk versus lower risk, as we try to think about tailoring therapy.

Essentially, where we stand with DETERMINATION is that this study started actually over -- my goodness, the concepts behind it started in 2008. That's almost 14 years ago as we developed RVd. We felt that RVd, which is lenalidomide, bortezomib, and dexamethasone, was at that time, our best platform in the upfront setting where we got 100% response rates, 50% complete response rates. We were really encouraged by what we saw.

When we combined it with transplantation, the response rates were actually interesting enough not particularly different. But having said that, there was a clue that progression-free survival for transplant might be that much more impressive than we perhaps had seen from just the RVd alone.

The other key question that was front, middle and center of our minds, Jenny, was that maintenance was a burning question with the role of lenalidomide, looking to us like it should continue until either it ran out of benefit or it became less tolerable. Whereas, our European partners were being forced primarily by their regulators to limit lenalidomide to just one or two years at most.

The background to the study is really RVd with or without transplant with lenalidomide maintenance, being at that time a kind of new world to explore. We partnered with our French colleagues. We launched the studies in 2010.

It was amazing to have to report the data 12 years later because on the one hand, that spoke to the very success of the studies, or particularly our study, the French study read out significantly earlier, but at least to which because the maintenance was just one year, ours was not.

But also, that the progress in the field, Jenny, I remember 10, 15 years ago, we reported on the VISTA trial within a few years of it starting. Within three to five years, we reported on this which is VISTA, which is VMP just for people's historical context. That was on newly diagnosed patients. Now, with the newly diagnosed younger population, we have to wait 12 years before we report data. That's a real sign in itself of success, Jenny. That was a background to the study.

Jenny: That’s incredible. But it takes that long for a readout.

Dr. Richardson: Exactly. I think that's the good news from the work amongst many other things. The other thing I wanted to share with you, Jenny, is that this was a study conducted across 56 centers in the United States. I want to especially acknowledge the contribution of all of those centers and the research nursing teams and clinical research coordination teams at these centers because those are really the folks who are the engine rooms, if you will, of successful research.

In order to do that, we had partnered with our pharma partners who provided us with free meds, and which was incredibly important, and also the resources to get the job done. We had a great clinical research organization. We conducted no less than 28,000 monitored visits. We continue to do that to provide really high-quality data to be sure that the data we report to you, Jenny, are accurate.

We ran this all from Dana-Farber with the support of the wonderful Clinical Trials Network, the CTN, who supported the trial, and also the endorsement and support of the so-called Alliance. I actually just finished my ten-year term as the chair there.

In the course of the study, we got the endorsement of the Alliance which was critical. At the same time, I want to especially acknowledge my colleagues on the Myeloma Committee at the Alliance who also was so supportive. We've lots of support from various centers including the NCI Pharma.

This is a really nice story, Jenny. We had philanthropic support. We could not have done the trial without the support of the R.J. Corman Multiple Myeloma Research fund. That fund in particular was central to the success of the program. We enrolled 722 patients over the course of eight years from 2010 to 2018.

Then, four years after the last patient was enrolled, we were able to get some readout because our steering committee had been very careful about making sure that we could only read out information when we really had full information around prespecified statistical endpoints to report to the audience or to the myeloma community. This is the background to the trial.

Jenny: That’s wonderful.

Dr. Richardson: I'm sorry. If you'd like, I can go into the results and talk to you about those.

Jenny: I would love you to go over the results.

Dr. Richardson: Please feel free, for our listeners, to jump in with any comments. In terms of the patients enrolled, these patients were aged between 18 and 65. We did set the cutoff at 65 because our French partners have strict rules in France that patients over the age of 65, it's much less easy for them to have access to autologous stem cell transplant.

Just to remind patients and listeners, I should say, the design of the trial, we looked at RVd followed by stem cell collection in both arms of the study. Then once the RMA as we called it, which was the RVd-alone arm, then went on to get another five cycles of RVd. A total of eight cycles of RVd followed, by len maintenance continuously. Zometa was given throughout, and Arm B, which was the transplant arm, so a nice acronym there for the bone marrow transplant, Arm B.

Arm B received three cycles of RVd stem cell harvest, then an autologous stem cell transplant, two cycles of RVd, and then len maintenance afterwards. Obviously for Arm A, if the disease came back, they had the option of stem cell transplant. But importantly, we didn't mandate it. We recommended it. But we said, if for reasons you’re a caregiver, you did not want to do a transplant, if at some point, if you could do it, that would be great, if you needed it, if it was appropriate. But if you couldn't, or you didn't want to have it, you could obviously have other treatments as well.

This was an important caveat because obviously in the U.S., we have choices. What we didn't want to do was straitjacket patients into force choices. We wanted to make sure they really had a choice. But at the same time, we recommended a delay transplant for Arm A if unfortunately, their treatment failed them.

That was the basic design of the study. As I mentioned, we started in enrollment at the very end of 2010 and finished enrollment at the very beginning of 2018, January 2018. We were blessed because we had remarkable participation across the country, but we got the highest number of African-American patients to participate in any myeloma study to date at approximately 20%. We were very pleased to see that.

Jenny: That’s huge.

Dr. Richardson: It was huge, because it I think was also a measure of with how patient-focus the study was that essentially, we were putting the convenience and tolerability, and out of bubble, the free medicines of course were very important to provide to our patients so that they could get the maximal benefit. That also allowed absolute complete access to the modalities offered rather than any kind of selection processes that might go into that. A unique study in many respects.

Jenny: Can I make a comment just about that? Just about clinical trial study design. I think it's really important to just highlight the design, because having a flexible design that is attractive for patients to join is really essential. What you did, you provided this very open structure like you were mentioning before, and it made it attractive enough for patients to join. I think that's part of the strategy, I guess. What you found in your African-American patient participation is the better study design you have, the more likely patients are to join, which seems obvious, but it's important. Not all studies are designed like that.

Dr. Richardson: Thank you, Jenny. I would also very much acknowledge the centers because essentially, we went to centers right across the U.S., the south, the west, the east, the Midwest, and also the big urban centers, such as Detroit in Chicago and so on.

Basically, I think you're absolutely right. What we did was provide a practical real-world therapeutic platform. Of course, the real benefit of a patient and user -- and what I mean by user, I mean provider-friendly schedules, but also rigor. We did insist that patients were monitored extremely carefully for safety, extremely carefully for outcome. We've built important correlative science into the study. We're very grateful to our patients for doing that and participating.

We did bone marrows to assess response, presence of secondary problems from the transplant, because that's something we uncovered which was this issue of secondary leukemia. At the same time, looking at a very important outcome which was so called MRD or minimal residual disease.

As part of our correlative science, we also focus in some very new age, I should say, technologies including whole genome sequencing to better understand patients’ disease and really start to get to the bottom of why tailoring therapy is important. To use a simple metaphor, one size doesn't fit all.

I want to acknowledge, actually, we had a very good steering committee led by colleagues from both France and the United States. We had a data safety monitoring committee as well that was also international. It was very kind of you to mention the Kyle Award because actually one of the chairs of the DFMC was, in fact, no less than Dr. Bob Kyle. The other chair was a wonderful leading myeloma specialist, Dr. Joan Bladé from Spain.

But in any event, they also had some very good statisticians in the group. That meant we had really good input from our DFMC guiding us very thoughtfully about the trial. They required us to keep going with the analysis until we have what we call full information which gave us maturity of information in any estimates that we then derive.

The important other pieces that our French partners, with one year of maintenance, had to call their results in 2016. The French one, a remarkable study group called the Intergroupe Francophone du Myélome. In that study, it's called the IFM. The only way to get access for most French myeloma patients to treatments is to participate in the IFM. That means that they enrolled very quickly to this study in France because obviously, for most ordinary French folks, you couldn't get into the RVd based treatment unless you participate in the trial. This allowed them to move very quickly.

I must say, frankly, with enormous affection and respect for my French partners, I much prefer the American model where patients really have choices. But the bottom line is that in France, if you need access, for most people, participation in the IFM is very vital. The good news is the IFM provides such high standards of care and exceptional options. It's a win-win.

But again, because of that, the IFM enrolled very quickly. We enrolled more slowly. Then, they were able to report earlier. Because as we learned, the reason probably for that was because lenalidomide maintenance was only for one year by the direction of their regulators.

In any event, what they showed was that transplant generated a progression-free survival benefit of about one year over standard of our RVd alone. Using in the French study delay transplant in about 80% of patients, there was absolutely no difference in survival at eight years of follow-up between delayed transplant and early transplant. What they also showed was that if you achieved MRD negativity, that was very helpful. Our French data were very, very helpful.

Our data however came out in a very fascinatingly and very different ways. This of course points to the difference in maintenance. First of all, we allowed lenalidomide to be used until progression and/or intolerance. We were so pleased to see our transplant arm generate the best progression-free survival we had yet seen. This was substantially better than what we've seen with the French patients who received an early transplant almost improved it by almost two years, where the median progression-free survival was 67 months. Really impressive results for the early transplant arm.

Very interestingly for our RVd-alone arm, we also saw the best results for that without transplant with a gain of about one year versus the two years seen for the early transplant arm, and about 48 months. This was really fascinating because obviously, there was a difference in favor of the transplant arm and progression-free survival of around 21 months which was great. Obviously, highly statistically significant.

Clearly, the primary endpoint of the trial was met, which was that early transplant provided progression-free survival benefit. But what was so interesting, and this is the key finding in my opinion, with median survival over 76 months. In fact, now, well over 18 months and beyond the survivorship between RVd-alone and RVd plus early transplant was exactly the same at 80%. Great results for both arms, but no difference in overall survival if you do early versus delayed approaches.

What was so interesting as well, Jenny, was that the use of delay transplant in the RVd-alone arm was actually just 28%. Seventy two percent of patients received other strategies, new treatments, and yet, at least so far, the survival looks to be identical.

This was incredibly important because what it meant is that patients really have choices on the one hand. On the other hand, we saw the best progression-free survival with both approaches that we'd seen in this setting. But the progression-free survival benefit to early transplant was really quite striking.

Jenny: That’s so fascinating. Now, we have so many other therapies that you're working on with these immunotherapies and things like that. For newly diagnosed patients with these results, do you suggest them going to early transplant? Or were there any subgroups inside of that trial that you realized were going to perform better with the early transplant?

Dr. Richardson: I think you lead to a very important point, Jenny. I think before diving into that in a bit more detail, it's probably well worth sharing with our audience some of the good things we saw, but also some of the challenges.

For the early transplant group, clearly, it was a more toxic approach. We saw a significant amount more toxicity with the early transplant. Fortunately, all expected, but nonetheless significant. We've incorporated quality of life. We showed that quality of life early transplant took a highly significant drop during the transplant procedure that lasted several months in fact. But the good news was that it recovered really nicely. Over time, the quality-of-life estimates between RVd-alone and RVd early transplant were identical.

There was, in fact, even some evidence of a rebound effect of post-transplant which might reflect the fact that patients really didn't feel at all well during the transplant, but rebounded nicely to feeling that much better post. But I think that's an important thing for patients to remember, because I think as providers, we can sometimes gloss over some of the tolerability issues and forget that from a quality-of-life point view, these things really matter. I think that's an important caveat.

The other challenge that we unearthed was the secondary malignancy story. The second cancers were equivalent in both arms overall, but the rates of hematologic cancer were higher for the early transplant group, and in particular for AML MDS which is a well-recognized risk to melphalan because of its genotoxicity. But because of the uniqueness of melphalan, it's obviously an incredibly important drug, but its downside is that it's genotoxic or mutagenic is the term.

As a result of that, we saw ten cases of AML MDS in the early transplant arm versus none in the delay transplant arm or RVd-alone arm. This was actually statistically significant. As you can imagine, the numbers were small, so that’s the good news, but this had a P-value of .002. It was an important finding.

I think that when you think of toxicities, think of quality of life, and you think of the secondary malignancy challenge, I think these are important cautions, but having said that, still, this PFS advantage is so substantial, is so impressive.

Now then, the next question that arises from all of that of course, in that context, Jen, is something of the following which is, what about responses? What we saw was actually very interesting. We saw that if you got really high-quality responses with either arm, you did just as well as each other.

What we showed, at least so far, that if you achieve MRD negativity on RVd-alone, your progression-free survival was the same. If you achieved complete response actually, the outcomes were very similar. Partial response or less than complete response was a little bit less clear. In fact, clearly the transplant did better if you only achieve the PR. The MRD-positive patients did do better with a transplant versus those who are negative. But what was very interesting is that the MRD-negative patients or those patients with very high-quality response appear to do just as well however they got there. These are important considerations as we go forward.

I think the critical point to your question, Jen, about what do you recommend, is that can be highly tailored. Because I think the important point for the audience now is that we designed this trial in 2008. We now have RVd Dara. We have KRd Dara. We have RVd isatuximab, KRd isatuximab. The MRD rates from these platforms without transplant goes high as 70% or 80%.

With those kinds of data, how to position transplant has moved into yet another question given that kind of data. But still, the DETERMINATION trial is incredibly helpful, I think, because it gives you clues as to who may need a transplant early, and who in fact you can afford to wait and see given both the pluses and minuses of the high dose melphalan.

Jenny: Right. When you think about strategy from a patient perspective, you're thinking, well, if the overall survival might be the same, but if I can get better progression-free survival and I don't have to worry about retreatment for a while.

Let’s say I have a high-risk feature, and I'm still MRD positive after that first induction therapy, then maybe that's the right move for me just to get out so everything can get through these clinical trials, and then I might be able to take advantage of another therapy once I relapse at that point, but my relapse timeframe is just longer. All right. I have a longer period of time until I relapsed.

But if not, and I'm getting MRD-negative, because I did a quad therapy now up front with RVd as the backbone, then maybe that's my strategy. I don't know. This is the reason that I think all patients should go see a myeloma specialist. Because of this very reason. It's a lot of strategy. I think you are uniquely qualified to help with that, determine that initial, especially initial strategy.

Dr. Richardson: That's so kind, Jenny. I would 100% agree with you. That’s strategic thinking now, thank God for myeloma is now the way to go. Because honestly, 20 to 30 years ago, it was purely tactical. We had median survivals of two to three years and non-transplant eligible patients, median survivals in transplant, eligible younger patients, the best three to five years.

Those are where you have to be tactical. You just want to throw everything at the disease because you've got nothing to lose. Now, we can be far more tailored, and as you put it so nicely, far more strategic. I think you summarized it beautifully, Jen. I think clearly transplant has a role. I mean for those high-risk patients who are not responding well, and you've got to cyto reduce and target stemness so much the better. However, there are substantial numbers of patients who don't fall into that category.

Again, if high-dose melphalan was without side effects and without long-term consequences, we wouldn't be having this conversation, but the problem is that high-dose melphalan, I think, and particularly speaking for myself as someone who had the privilege of working with some of the founders of high-dose melphalan not least of which Professor Tim McElwain at the Marsden, and being a transplanter myself for many years, I would say that it is a double-edged sword. It is a drug which provides a tremendous benefit by targeting stemness, but at the same time, it's side effect profile is real.

I think what's particularly important for us, as investigators, to understand is why do we see such a tremendous PFS benefit, which I so agree is a bridge to next steps. But we also have to ask ourselves a key question. Why is there no obvious overall survival gain? Now, it may be that we don't have a long enough follow-up, Jen. That is possibly true, but obviously, we'll know over the next several years. But the survival curves do look very stable.

My statisticians who are really brilliant leaders in the field and Dr. Edie Weller and Dr. Susanna Jacobus, as well as our statistical oversight from the DFMC, because do appear very stable now, that doesn't mean that it can't change. They may well do. We don't know. But we're at mature follow-up. I'm very reminded that the French data were at eight years median follow-up. They're also seeing no difference. Although, of course the critical thing is that transplant was used in 80% of the patients with salvage. They could simply say the transplant leveling the playing field.

I would say in our data, it was the opposite, right? I mean 28% got transplant, 72% got novel treatments. In those novel treatments, clearly, there's benefit because otherwise, we wouldn't see the survival be the same.

That's led us to dig even harder and say, well, is there a downside to the melphalan and that we don't really understand? What we’ve unearthed is something very important which is that because melphalan is mutagenic to stem cells, unfortunately, if there are surviving myeloma cells, they can also be stirred up genetically by the melphalan. There is mutagenic -- mutagenicity, I should say to the melphalan itself.

Now, we've cut that all the time in treatments. Many of our drugs are DNA damaging or turbulent to the DNA. The next question is, what does that do? What we found from our French partners is that we can magnify the mutagenic or the mutational burden in the surviving myeloma by up to fourfold with melphalan versus without it. Why that's so important is because we're trying to better understand the consequences of this.

Now, on the plus side is that if you make a cancer more genetically unstable and increase the genetic mutations within it, sometimes, the immune response can be better at detecting this and eliminating it. This may be why we definitely see some patients who clearly get tremendous benefit from transplant.

Conversely, however, and as we know unfortunately only too well for myeloma, it is truly multiple myeloma. There are so many different aspects of the pathobiology in each individual patient and across patients. If there's no big survival advantage with such a big PFS game, my biostatisticians have told me, clearly, that that suggests there may be competing risks.

We're trying to better understand what that means. Are there patients who clearly were stirring up the genetic part of their myeloma, and they may actually not benefit from high-dose melphalan to the same extent as others who really might?

Jen, you touched on this beautifully because you said there's subgroups in whom we saw benefit versus not. We did do a comprehensive subgroup analysis, but this was exploratory. It was not powered to be definitive. That would have taken a study twice the size. But what we did learn was some fascinating things that first and foremost, almost all the subgroups got some PFS benefit from early transplant that we looked at, but certain groups did not and/or was very much close to the median of one as we call it.

Very interestingly, we saw there that certain patient groups got more benefit than others. Again, these are hypothesis generating versus others. We found that certain genetic subgroups seem to do better and others less so.

For example, if you had 17p disease, the amount of benefit from the high-dose melphalan was surprisingly not what we expected. Conversely, if you had translocation 4;14 in your genetic makeup, we saw that the PFS difference was really quite impressive. This correlated very nicely with IgA. But 17p, it really didn't. They came back towards the middle. We have to be careful how we make sense of that because what it tells you is that one high risk patient is not the same as another.

Then we saw a fascinating finding that if you had very high body mass index, then your transplant may not be the right choice for you. But if you were, excuse the term, Lance Armstrong, you'd be transporting quite well.

Very interestingly, in terms of other patient subgroups, we also identified a few other fascinating features which may point also to differences in pathobiology. We touched earlier on really gratifying participation of African-American patients. What we saw there, which was remarkable actually, was that amongst African-Americans, the benefit of transplant was much more limited in terms of PFS.

In fact, their hazard ratio was just above one. Even though it tells you so much about the biology of myeloma, that it really is different, and it varies from patient to patient. We have to think about, I guess, I don't want to sound too metaphorical, but it really does bring us back to what I said earlier which is that one size clearly does not fit all.

Jenny: Absolutely. I have a general question too, because we've been looking at our HealthTree data as well. We're noticing that when patients are relapsing and when they show indication of relapse -- an official relapse is this .5 of your M protein, right? But we're seeing physicians treat at .1, .2, our average is .36.

When you're talking about genetic instability, does the earlier treatments like -- I've had one myeloma specialist tell me, a third of patients, their M protein will go up and then it will go back down. Another third of patients that will go up and it'll stay, and another third of patients that will go up and keep going up, so you want to treat those patients because they're obviously relapsing.

But when you talk about genomic instability and the transplant, when you see these patients, now you have very long-term follow-up data for the 72% of patients who did alternative therapies and not a salvage transplant, do you see the same thing like the more treatment we get as patients the more mutational burden we're getting regardless of the therapy? It's concerning me that everyone might be treating too early. Anyway, I just want to get your thoughts on that since it's a side question.

Dr. Richardson: Jenny, as always, your questions are spot on. I would argue it's actually not a side question. It's a central question. I think the bottom line is that we have to remember that basically, we have a really key set of issues to consider.

One, that it’s the nature of treatment. That's important. Basically, it's really important to understand this. Basically, it's a couple of things to share here that there are certain very genotoxic therapies. At the same time, these genotoxic therapies are perhaps more toxic than others. Obviously, alkylation remains a very important part of what we do. I think it's important to share that.

I think that the other piece of this is that there are immune treatments where this genotoxicity may be far less. I think your question is central. But I also want to emphasize that I don't want patients to think, oh, my goodness. Alkylation is bad. It isn't. It's absolutely essential for targeting stemness. The question is, how do we best do that? I guess the question is also that different patients have different vulnerabilities.

To your point, treatment, when it's needed is needed. I think that it's very important to think of it in that regard. I do think that it's basically very important to think of it in these terms because at the same time, we have choices. I think that's the critical point, Jen, that we have lots of choices. In that context, we have an opportunity to then tailor treatment to each individual patient.

I think I would argue alkylation is a key part of myeloma management. It absolutely is. Cyclophosphamide, melphalan, and of course the exciting new peptide-drug conjugate, melflufen. These are critical drugs in my opinion. I think at the same time, using them sensibly in a way that doesn't magnify risk and optimizes benefit makes a great deal of sense.

The melflufen experience is one very good example of that, Jen, where using melflufen immediately after transplant has failed, was not helpful in my opinion. That is not a smart move. It showed it in the OCEAN trial. Whereas, however, using it in patients where they hadn't been exposed to lots of chemotherapy, it would perform extremely well. I think the way I'd look at it is we've got 15 new drugs and modalities. We've got the opportunity to use them judiciously. We need to know how to use each tool in the toolbox more appropriately.

Jenny: Just while we're on the melflufen topic, that got put on hold. Because of that, they found that what you just said, patients who had had prior transplant or something, it wasn't good for those patients. For patients who have not, it was very effective for them. Now, it just got European approval. They might circle back around and try to do that in the United States again, right?

Dr. Richardson: I think the important message here is that it's a question of looking at this intelligently, isn't it? I think that there was some regulatory decisions made around the OCEAN trial which I completely understood given some of the challenges and the regulatory environment that exists particularly if an accelerated approval has been granted.

I think the challenge here was understanding patient subgroups. What is so important in the OCEAN trial is this was a head-to-head study. At the same time, in that context, the important message here is that the use of melflufen in patients has the advantage of what's called a peptide-drug conjugate. It basically doesn't cause alopecia or mucositis. It also has the advantage of a once-a-month infusion essentially because it delivers an incredibly targeted way, the melphalan warhead. It delivers a very lethal dosing to the tumor.

What's also so interesting about melflufen is that it actually appears to be very uniquely able, in the preclinical setting at least, to nail 17p which obviously, traditional melflufen struggles with. It’s able to leverage an enzyme system called the aminopeptidases which are uniquely overexpressed in myeloma. That explains why for example it is on target, so you don't get hair loss and mouth sores and so forth. In any event, it does cause side opinions. We have to be thoughtful about that.

But to cut a long story short, in the OCEAN trial, the subgroup of patients in whom it probably is not wise to use it, didn't unfortunately skew some of the results in the statistical sense. As a result of that, the EMEA took a very different look at this data, insisted on new data information. When they found all of that, they were very pleased, and then they recommended for approval.

I'm very pleased to report my understanding that the FDA is taking a fresh look at this now. I'm very hopeful with the new data that's been generated around this central question of subgroups and be able to bring up what I consider this important drug forward, not least of which because of course, it's so useful in the COVID era, right? It's an outpatient therapy. It's particularly good in the elderly and so on. For lots of reasons, I'm very hopeful it'll be there for our patients to benefit from.

Jenny: Okay, great. Now, I know the time goes so quickly. It's crazy. Would you mind giving a broad overview of CAR T updates, and maybe by specifics, it seemed like there was quite a bit of bispecific antibody data at these meetings. Then, you may have other comments that you want to make about other immunotherapy type things like CELMoDs or other things. I know you had a COVID study you wanted to share. Anyway, I'll let you do that in whatever order you want to do. We’ll go at the top of the hour, but you have a lot to still talk about.

Dr. Richardson: It's absolutely my pleasure. I mean I think, essentially, the important messages from the meetings at ASCO were really amazing. Let's quickly run through the list for our listeners.

You mentioned, I think we touched on this in the list, there was obviously the excitement of some of the quadruplet data. Dara-KRd is an induction treatment that was really nice data. I mean, recognizing that carfilzomib is more powerful than bortezomib. Generally speaking, we just have to be very careful about its vascular signal. But it's an incredible PI. The Dara-KRd data seemed to really support that.

I was also very excited at the meetings honestly to see how belantamab mafodotin was delivering. We've gotten a much better handle around the oculus side effects. That has been really something that was a challenge initially. But as we've gotten to be able to deliver the drug every six to nine to 12 weeks, it's even better. It's been shown that you can by giving it less frequently and especially in combination, generate really great outcomes with much less of a worry regarding toxicity.

I think what to me, personally, has been so encouraging is that belantamab mafodotin’s keratopathy, this ocular side effect, is reversible. It is not something which leaves people with, in my experience, any kind of permanent issue. If you see it, you manage it, you reduce schedule in dose you can consider reducing dose, and with really good eyecare. I've been very pleased with how it's been performing and seeing some great responses.

Then dropping into the CAR T space, I think you're absolutely right, Jen. There's so much excitement around the ide-cel, cilta-cel, the Abecmas, the ide-cels called the CARVYKTI. Here’s an amazing name for cilta-cel. CARVYKTI, I guess it makes a lot of sense though if you think of it as CAR T. But anyway, the data obviously are very promising. I think the challenge has been availability. CAR T's are very difficult to access commercially in my experience. The waiting list that we were told about at the meetings from real-world experiences, not just anecdote, but real-world studies, median wait time is six months. That, obviously, is very sobering.

I think going forward, we have to think about, as a healthcare community, in the myeloma community, and the healthcare system, how can we improve upon that? That's a challenge. I think, what we've also realized is whilst we've seen wonderful results with both platforms, the duration of CAR T benefit remains a major issue. Clearly, it seems to be longer for cilta-cel versus ide-cel, but the data of around one year for ide-cel or maybe two years or perhaps a little bit more for cilta-cel, there's a great data and very promising for selected patients. That's what we're seeing.

But in real-world practice, we're also seeing some of these be much shorter. I think we then need to think how can we, again, level the playing field with these approaches. I think in that context, there are a lot more exciting ones coming. I think that's important. I think also, that the important thing also beyond that is that the bispecifics of course are coming into the space and showing us a real off the shelf approach. Although I want to emphasize there’s off the shelf requiring hospitalization and there's off the shelf not requiring hospitalization. I think that's a distinction that’s important for providers and patients alike.

But I do want to pivot back to the question around some of the CAR T toxicities. Because I think, we've been very impressed that ide-cel may be generally better tolerated than cilta-cel, and a lot of the side effects are becoming easier to manage. But I think that we need to be very thoughtful about the long-term consequences we're seeing.

There is this real entity of this late onset CNS toxicity seen primarily with cilta-cel, but there are now reports with ide-cel as well. This is something we need to better understand. These are Parkinsonian syndromes which appear very difficult to treat. Speaking personally, I've lost one of my patients to that recently.

I think that it's really important to better understand these because obviously, to have dramatic results in the majority of patients is great. But also, if you happen to be one of the patients who runs into this long-term problem, that can be obviously devastating. I think we've got a little bit of work there in figuring these things out. Like a lot of things, the promise is there. But also, we have to make sure that we're very cautious about the reality, if you will, for want of a better term.

I think these additional targets that you and I discussed before, Jen, are really important then because BCMA, obviously, is great. But there are other targets like GPRC5D. There may be another one that doesn't have this CNS issue, but may be equally -- very exciting to pursue just as an example.

Going back to the bispecifics, we've got teclistamab, obviously right on the cusp of approval. That's extremely exciting. The data presented at the meetings was superb in my opinion. The one caution I have about the teclistamab data was the high rate of COVID-19 mortality that was clearly seen.

Jenny: I saw that.

Dr. Richardson: The argument that somehow, but just because of COVID-19 pandemia is a little bit strong because, for example, we presented data from the Alliance at EHA led by my colleague, Peter Voorhees, where during the pandemic, we use this particular platform. It was ixazomib pom-dex versus pom-dex. In this randomized Phase II trial, ixazomib pom-dex performed very well. It was very safe. We didn't have a single COVID-19 death. Our PFS rate for pom-dex was 21 months almost, just shy of it. The control group was seven and a half months.

You've got a lovely oral platform, very convenient for the older folk, frailer folks. Look at that PFS, it's terrific. I mean great. I want especially knowledge Pete, actually, because that was a long journey with that particular trial.

But you see my point, Jen, that we need to be very thoughtful about some of these toxicities because clearly, the teclistamab data are in a much sicker population, so that has to be said. But nonetheless, of 160 or so patients, at least ten dying from COVID. We need to be able to think about that and take that on and prevent that from happening.

Jenny: That just brings up a question because the bispecific antibodies seem to be very effective that you're on them for a long period of time. When you think about infection, how do you reduce that infection risk whether it’s COVID or anything else? Those are some of my thoughts about, just be careful about how you're using it and how long do you need to use it?

Dr. Richardson: Yes, I think that's a great question. It's really vital that obviously, you have to recognize, I'm afraid, that COVID-19 is, as we've moved from pandemia to endemia for our myeloma community, COVID-19 remains a significant challenge. I think that we're working hard with new treatment strategies to minimize some of the endothelial components of the disease which actually may be terribly important.

For example, the toxicities around the bispecifics where the mortality seems to be high. But also, there are obviously other therapeutic approaches that are very important in managing COVID-19. Infectious precautions or options like IVIG can be very, very important in that same context.

I think that the important construct here is that as patients and families think about COVID, obviously, we need to continue to be vigilant. We've got great new tools in the toolbox, not only the boosters and the vaccines, but also neutralizing antibodies like Evusheld which I recommend to my patients every six months.

Then of course, we've got Paxlovid as a therapy which is oral and not easiest thing to do actually, but three tablets twice a day for five days. Sometimes, you have to repeat it because you can get this rebound effect. Although you can get a very metallic taste from the pills, my patients, and there are also some patients who report a little bit of diarrhea, it's generally okay. You just have to be very thoughtful about what other pills you're on at the same time.

But I do think we've gotten better at managing COVID. That is for sure. I don't want people thinking that the death rate from COVID means you shouldn't get a bispecific. I don't think that's true, Jen. I think, however, we need to think thoughtfully about the bispecifics as we recognize the challenge of COVID-19. But I do think it's manageable to your point.

Jenny: Well, it makes sense. There are a lot of strategies. I know people are thinking about, do we use them before CAR T, after CAR T, and all that. I'm sure that will play out when the data starts coming out, and using them sequentially, and really shooting for more of a curative approach.

Now, you wanted to talk about also CELMoDs. I know those are in development. I don't know if they'll end up replacing like the Revlimid and the Pomalyst of the world. But maybe, you want to give us an update on that as well.

Dr. Richardson: I'd be delighted. Thank you for asking for that, Jen, because the CELMoDs obviously were not necessarily front, middle and center of the EHA and ASCO meetings. But I'm very hopeful we'll be hearing more in the myeloma research community at the meeting certainly at IMS and also at ASH.

But in a nutshell, the iberdomide program has continued to gain momentum. That's been shown great results in combination. These are cereblon E3 ligase modulators, and just that much more potent than immunomodulatory drugs. Also, interesting enough, may be associated with less risk of second cancers which I think is an important positive, preclinically anyway, a very important positive. But preclinically, it does appear to be true. If that's the case, that's great. In fact, in case clinically, we'll obviously have to see, but I'm very hopeful.

The other CELMoDs is of course a CC-92480. Iberdomide used to be called 220. We've traditionally called CC-92480, 480. But that has a rather catchy name of mezigdomide.

Jenny: Oh, nice.

Dr. Richardson: Well, it’s a little tricky, Jen. Mezigdomide. But I call it mezi for short just because I think that's a little bit easier. Mezi is a very, very exciting news somewhat in my opinion, because it's that much more potent than iberdomide. Mezi is also very active in extramedullary disease which is such an important thing.

We kind of christen this in my team, CAR T in a pill. You can just take three weeks on and one week off of a mezi, especially in combination and see really good results with it. But obviously, that's in combination in early days in highly carefully controlled clinical trials. Lots of work still to do. But we're very pleased even the triple class are resistant in BCMA exposed population. We're seeing really nice response rates. The advantage obviously of the pill speaks for itself. I think that's great. The other thing is we're seeing a very low rate of COVID mortality as well to our earlier points.

Jenny: Do you think there will be a day where we see a CAR T upfront or something like that? Then use of some drug like this, like mezi, as maintenance therapy or taken to maintain the response, if that's modulating the immune system and keeping it going after the myeloma?

Dr. Richardson: I think that's a lovely thought. I think CAR T coming up front is very exciting because obviously, it will hopefully be much better tolerated earlier and not that they're necessarily not tolerated. But sometimes, it can be challenging as we discussed. Moving CAR T earlier could be very exciting for selected patients.

I have to say though, I think as we think about CAR T going earlier, we touched earlier on the BCMA target and some of the late onset neurological things we're seeing, I do think we have to be very thoughtful about that. As long as that's a problem we can overcome, and it isn't a long term issue that grows over time, I think that that will be very exciting for bringing CAR T earlier.

I think your points are well taken that cellular therapy is working with a better immune system, have a real promise. I do think, in that space, we talked about natural killer cells for example, that's another area of real promise coming in terms of the new pipeline. I think I see in the world where we have cellular therapy which essentially mimics an autologous stem cell transplant, and then follow it with an enhanced CELMoD, I think that's very possible. I think strategically, probably, iberdomide will be the right choice for that earliest slot, with mezi perhaps kept focused.

We also have to think strategically, Jenny, as you and I talked about before where we've got to have fallback positions in case our initial strategies fail. I think that's another reason why I'm so excited about some of the other agents that were profiled at the meeting.

One that you touched on, and I appreciate you mentioning it, when we were having our conversations over the weekend, there are these so called immunoconjugates. The best example of that is TAK-573. That's actually a trial being led by my colleague, Omar Nadeem. We're very pleased with what we're seeing with that particular approach. I think there are lots of different options available. The pipeline continues to be rich. It allows us to really optimize what I call an individualized approach to patient care.

I do want to pivot back to a point though you meant about bringing CAR T earlier and following it with CELMoDs. I think that's a really interesting idea, and somewhere we're going for sure. I think the other part of this is this whole construct of targeting will be called stemness. That, again, because I don't, in any way, want to diminish what we learned from determination. We saw in determination that melphalan mattered. It does matter. Clearly, targeting stemness matters. As we think intelligently about that in the future, that's going to be important too.

Jenny: Wow. Dr. Richardson, you've given us a lot to think about. We have so many options in myeloma. It's a massive blessing to have this “problem” that we have about being able to decide. But I just want to reiterate that it's because of specialists like you who are doing these studies in all these different iterations to figure out what is the best therapy for each individual patient that we’re coming to these conclusions?

I thank you so much for joining this call and for giving us an update. We could talk for probably three hours on this topic, I think.

Dr. Richardson: I think that’s absolutely fabulous. As always, Jen, it's truly my privilege. It's lovely to talk to you. Thank you for all your super questions. Above all, a big thank you to your audience.

Just as I say, I'm privileged to be part of the myeloma research community, and to see the continued progress. I really would just above all, want to acknowledge everyone who's contributed to our research and in particular that I think about the DETERMINATION study, it's impact. That's all because of everyone who's contributed. I just wanted to close by thanking everyone. Above all, our patients and families.

Jenny: Thank you so much for leading out in the fields of multiple myeloma. We're just so appreciative of everything you do. Thank you. I get emotional when I think about all the work and the effort that you're dedicating your life to help us. We just greatly thank you. Appreciate it very much.

Dr. Richardson: Jen, please. It truly is a privilege and an honor. I say that with the deepest of sincerity because I just realized how incredibly challenging everything is for our patients. On the one hand, I'm so lucky to see some of my patients do incredibly well. But I'm also so humbled when I see some of my patients, and patients I consult for or provide input, and I see them run into real difficulties even within two to three years of their diagnosis. You just realize that myeloma is one hell of a challenge. There's no question about that. We've come a long way, but I still agree with you, Jen. We still got a long way to go.

Jenny: Thank you for continuing the fight.

Thank you to our listeners for listening to the HealthTree Podcast for Multiple Myeloma. We invite you to join us next time to learn more about what's happening in myeloma research and what it means for you.